Endoscopic diagnosis and staging of mucinous cystic neoplasms and intraductal papillary-mucinous tumors.
The number of patients with cystic neoplasms of the pancreas as detected using various types of imaging techniques has been steadily increasing. Among the cystic neoplasms, mucinous cystic neoplasms (MCNs) and intraductal papillary-mucinous tumors (IPMTs) were comparatively more frequently encountered. We used imaging techniques to focus on the differential diagnosis of MCNs and IPMTs, and tumor staging. Fifteen patients with MCNs with ovarian-like stroma and 109 patients with IPMTs were experienced. We examined the image findings for the differential diagnosis and stage diagnosis of these two types of cystic neoplasms. Endoscopic ultrasonography could reveal detailed images of internal structure and was effective for the diagnosis of MCNs. Other endoscopic imaging modalities could not give specific findings for MCNs. Endoscopic retrograde cholangiopancreatography (ERCP; including duodenoscopic findings and pancreatogram) and pancreatoscopy showed the characteristic and specific findings of IPMTs. Also, endoscopic ultrasonography and intraductal ultrasonography were found to have high sensitivity and diagnostic accuracy for their differential diagnosis of neoplastic/nonneoplastic and invasive/noninvasive lesions in IPMTs. Endoscopic imaging techniques are capable of revealing the detailed structure of pancreatic cystic lesions. They are effective for differential diagnosis, for assessing the degree of malignancy, and for deciding upon an appropriate treatment in patients with IPMTs.


Peptidomics: identification and quantification of endogenous peptides in neuroendocrine tissues.
Neuropeptides perform a large variety of functions as intercellular signaling molecules. While most proteomic studies involve digestion of the proteins with trypsin or other proteases, peptidomics studies usually analyze the native peptide forms. Neuropeptides can be studied by using mass spectrometry for identification and quantitation. In many cases, mass spectrometry provides an understanding of the precise molecular form of the native peptide, including post-translational cleavages and other modifications. Quantitative peptidomics studies generally use differential isotopic tags to label two sets of extracted peptides, as done with proteomic studies, except that the Cys-based reagents typically used for quantitation of proteins are not suitable because most peptides lack Cys residues. Instead, a number of amine-specific labels have been created and some of these are useful for peptide quantitation by mass spectrometry. In this review, peptidomics techniques are discussed along with the major findings of many recent studies and future directions for the field.


Induction of regulatory T cells by Opisthorchis viverrini.
Opisthorchis viverrini causes public health problems in South-East Asia. Recently, TGF-β and IL-10 have been reported to increase in O. viverrini-infected hamsters but the sources of these cytokines are still unknown. In this study, the CD4+ T cells in infected hamsters were investigated. It was demonstrated that IL-4+ CD4+ T cells were significantly increased in hamster spleens and mesenteric lymph nodes (MLNs) during chronic infection. Interestingly, IL-10+ CD4+ T cells were also discovered at a significant level while Treg (T regulatory)-like TGF- β+ CD4+ T cells were in MLNs of infected hamsters. Moreover, the CD4+ CD25+ Foxp3+ Treg cell response was significantly found both in spleens and MLNs in infected hamsters. The findings were then confirmed by development of T-cell clones against crude somatic antigens (CSAg) in immunized BALB/c mice. Five clones named TCC21, TCC23, TCC35, TCC41 and TCC108 were established. The TCC21 was found to be the TGF-β+ CD4+ while TCC35, TCC41 and TCC108 were IL-4+ CD4+ and TCC23 was IFN-γ+ CD4+ . This TGF-β+ CD4+ T clone showed an inhibitory function in vitro in mononuclear cell proliferation via TGF-β-mediated mechanisms. This study indicated that O. viverrini-infected hamsters could induce TGF-β+ CD4+ Treg-like cells. The CSAg-specific Tregs secreted high TGF-β, and limited immune cell proliferation.


Urinary tract infections and circumcision. A case-control study.
It has been shown that uncircumcised infants have a higher rate of urinary tract infections in the first few months of life. To investigate further the association between noncircumcision and urinary tract infections, a case-control study was performed of infant boys who had a catheterized or suprapubic urine culture done as part of an acute illness visit. Cases (n = 36) were those infants who had a positive culture (greater than 105 organisms per milliliter); controls (n = 76) had a negative culture (less than 103 organisms per milliliter). There were no significant differences found in the two groups in age, ethnic group, and type of medical insurance. All of the cases were uncircumcised, vs 32% of controls. The data were analyzed separately by age, ethnic group, type of insurance, and method of culture, and in all groups the cases were significantly more likely to be uncircumcised. Of the 31 cases who underwent roentgenographic investigations, 8 had abnormal findings. Noncircumcision seems to be a highly significant risk factor for urinary tract infection in infants up to 12 months of age, affects infants regardless of race and socioeconomic status, and is associated with anatomic abnormalities in 26% of cases.


Outcomes of After-Hours Hip Fracture Surgery.
Given single-institution studies showing trends between after-hours hip fracture surgical procedures and adverse outcomes, as well as fixation time targets that may increasingly compel after-hours operations, we investigated the relationship between after-hours hip fracture surgical procedures and adverse outcomes in a large, population-based cohort. All Ontarians who were ≥60 years of age and underwent a hip fracture surgical procedure between April 2002 and March 2014 were eligible for study inclusion. Data were obtained from linked health administrative databases. The primary exposure was after-hours provision of surgical procedures, occurring weekday evenings between the hours of 5 P.M. and 12 A.M. or over the weekend, but not overnight (after 12 A.M. to 7 A.M.). Surgical complications up to 6 months following a hip fracture surgical procedure comprised the primary outcome. Medical complications, including mortality, up to 90 days postoperatively were also assessed. Odds ratios (ORs) were calculated using a logistic regression model that accounted for clustering at the hospital level and adjusted for patient, provider, and fracture characteristics previously shown to explain the majority of variance in hip fracture outcomes. During the study period, 87,647 patients underwent an isolated hip fracture surgical procedure; 51.2% of these patients had femoral neck fractures, 44.1% had intertrochanteric fractures, and 4.7% had subtrochanteric fractures. The surgical procedure occurred after hours in 59,562 patients (68.0%), and 27,240 patients (31.1%) underwent a surgical procedure during normal hours (7 A.M. to 5 P.M.). Only 845 patients (1%) underwent a surgical procedure overnight. We observed no significant relationships between timing of the surgical procedure and adverse outcomes, except for patients who had undergone an after-hours surgical procedure and had fewer inpatient surgical complications (OR, 0.90 [95% confidence interval, 0.83 to 0.99]; p = 0.01). Adverse outcomes following a hip fracture surgical procedure were similar whether a surgical procedure occurred during normal hours or after hours. Concerns regarding the quality of after-hours surgical procedures should not influence hip fracture prioritization policy. However, given that the great majority of hip fracture surgical procedures occurred after hours, future research should examine other potential consequences of this practice, such as financial impact and surgeon burnout. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Retaining pathological gamblers in cognitive behavior therapy through motivational enhancement: A pilot study.
Treatment for pathological gambling is in its infancy. Several cognitive and behavioral interventions have shown promise, but high attrition and relapse rates suggest that gamblers requesting treatment are not uniformly committed to change. This article describes an exploratory study with 9 severe pathological gamblers--in their majority horse race bettors--who were recruited from a community treatment center. The gamblers were treated with a hybrid intervention consisting of motivational enhancement and cognitive behavior therapy. All gamblers were retained in treatment and during a 12-month follow-up period. This retention rate was significantly higher than that of a control group of gamblers who received treatment as usual in the same community setting. Of the gamblers who received the experimental treatment, 6 maintained total abstinence during the 12-month follow-up period, 2 were significantly improved, and 1 remained unimproved. In addition to changing their gambling behavior, many clients made successful lifestyle changes. The possible benefits of combining a motivational intervention with cognitive behavior therapy are discussed.


HIV viral suppression results in higher antibody responses in HIV-positive women vaccinated with the quadrivalent human papillomavirus vaccine.
To evaluate the immunogenicity and safety of the quadrivalent HPV (qHPV) vaccine in HIV-positive women over 24months. Between November 2008 and December 2012, 372 women aged 15 and older were enrolled from 14 Canadian HIV outpatient clinics in an open label cohort study. The qHPV vaccine (0.5mL) was administered intramuscularly at months 0, 2 and 6. The primary study endpoint was seroconversion to any of the HPV types targeted by the qHPV vaccine. Antibody levels were measured at 0, 2, 7, 12, 18, and 24months. Adverse events were recorded throughout. Of 372 participants enrolled, 310 (83%) received at least one dose of the qHPV vaccine and 277 (74%) received all three doses. Ninety-five percent (293/308) were seronegative for at least one vaccine type at baseline. The median age was 38years (IQR 32-45, range 15-66), 36% were white, 44% black and 13% were of Indigenous origin. Seventy-two percent of participants had a suppressed HIV viral load (VL<40c/ml) at baseline, with a median CD4 count of 510cells/mm(3) (376-695). Month 7 HPV type-specific seroconversion rates were 99.0%, 98.7%, 98.1% and 93.6% for HPV types 6, 11, 16 and 18 respectively in the per-protocol population. Participants with suppressed HIV VL at first vaccine had a 1.74-3.05fold higher peak antibody response compared to those without (p from 0.006 to <0.0001). This study is the first to examine the qHPV vaccine in HIV-positive women out to 24months and the first to include HIV-positive women through to age 66. The qHPV vaccine was well tolerated, and highly immunogenic. As women with suppressed viral load had higher antibody responses, planning HPV vaccination to occur when persons are virologically suppressed would be optimal for maximizing immune response. Findings provide strong evidence that older HIV-positive women can still benefit from HPV vaccination. http://www.isrctn.com/ISRCTN33674451.


Links between DNA polymerase beta expression and sensitivity to bleomycin.
Bleomycin (BLM), an important anti-tumor antibiotic, enables cell death through oxidative DNA damage mediated by reactive oxygen species (ROS). However, increasing cellular resistance has become a serious limitation to its clinical application. Base excision repair (BER), the major pathway for repairing oxidative bases, is involved in resistance of DNA-damaging anticancer drugs. DNA polymerase beta (pol β), a critical BER enzyme, has been reported to play a crucial role in combating BLM-induced oxidative DNA damage, as a result, pol β inhibition may increase the sensitivity to BLM. To test this hypothesis, we evaluated the sensitivity to BLM using mouse embryo fibroblasts (MEFs) with distinct pol β expression levels (wild-type, pol β deficiency) and explored the underlying mechanisms. The results showed that cell viability of pol β-deficient MEFs was significantly lower than that of isogenic wild type when treated with the same BLM dosage. In addition, increased ROS level, DNA single strand breaks, and chromosomal breakage were observed in pol β deficient cells, indicating impaired DNA repair and enhanced oxidative DNA damage under pol β deficiency. In agreement with the findings, an enhanced hprt gene mutation frequency was also detected in pol β null cells. In summary, this study demonstrated that BLM-induced DNA damage could be repaired through BER pathway and absence of pol β allows oxidative DNA/chromosome damage and gene mutation, which contributes to BLM hypersensitivity.


Rationale and management of hyperlipidemia of the nephrotic syndrome.
Hyperlipidemia is usually present in patients with the nephrotic syndrome. The most common lipid abnormality is hypercholesterolemia, although as the disorder progresses, hypertriglyceridemia may develop. Elevated plasma lipids have two potential vascular consequences, namely, atherosclerosis and progression of renal failure. Neither of these complications has been proven with certainty, but there is growing evidence to indicate that both may be long-term consequences of the nephrotic syndrome. Therefore, effective therapy of hyperlipidemia, particularly elevated cholesterol levels, is needed as a protection against these complications. Since nephrotic hypercholesterolemia frequently is severe, dietary therapy, although a valuable adjunct, will not normalize cholesterol levels in most nephrotic patients. Thus, if effective serum cholesterol lowering is to be achieved, drug therapy will be required. Bile acid-binding resins have been shown to lower cholesterol levels in nephrotic patients, but the decline in cholesterol concentrations is usually insufficient to produce a marked reduction in coronary risk. Nicotinic acid theoretically should be useful for treatment of nephrotic hyperlipidemia, but it has not been adequately tested. The new drugs that inhibit cholesterol synthesis, e.g., lovastatin, appear to be highly promising for treating elevations of both serum cholesterol and triglycerides in the nephrotic syndrome. However, testing of these drugs in this condition has been limited, and the possibility of significant side effects in an appreciable portion of patients has not been ruled out. Of particular concern is the development of severe myopathy that can produce myoglobinuria and acute renal failure. This side effect is relatively rare in patients without the nephrotic syndrome, but its prevalence in the latter condition has not been determined. The fibric acids will lower triglyceride levels in nephrotic patients, but they are not effective in lowering cholesterol levels; consequently, they probably have little role in the treatment of nephrotic hypercholesterolemia. Finally, the drug probucol will lower cholesterol levels in nephrotic patients, although not to desirable levels; still, probucol could prove useful in combination with other cholesterol-lowering drugs.


Does involvement in a cohort study improve health and affect health inequalities? A natural experiment.
Evidence suggests that the process of taking part in health research can improve participants' health, independent of any intended intervention. However, no research has yet explored whether these effects differ across socioeconomic groups. If the effect of mere participation in health research also has a social gradient this could increase health inequalities and bias research results. This study used the Born in Bradford family cohort (BIB) to explore whether simply taking part in BIB had improved participants' health and, if so, whether this effect was mediated by socioeconomic status. Survey data on self-reported health behaviours were collected between 2007 and 2010 as part of BIB. These were augmented by clinical data on birth weight. Pregnant women on their second pregnancy, joining BIB for the first time formed the control group. Their health was compared to women on their second pregnancy who had both pregnancies within the study, who formed the exposed group. In order to limit the inherent bias in a non-randomised study, propensity score analysis was used, matching on age, ethnicity, education and date of questionnaire. The results were then compared according to mothers' education. Of six outcomes tested, only alcohol consumption showed a statistically significant reduction with exposure to BIB (OR: 0.35, 95% CIs 0.13, 0.92). Although effect estimates were larger for women with higher education compared to lower education, these effects were not statistically significant. Despite one significant finding, these results overall are insufficient to conclude that simply taking part in BIB affected participants' health. We recommend that socioeconomic status is considered in future studies testing effects of research participation, and that randomised studies with larger sample sizes are conducted.


Antioxidant and choleretic properties of Raphanus sativus L. sprout (Kaiware Daikon) extract.
Brassica vegetables and glucosinolates contained therein are supposed to reduce the risk of cancer and to possess health-promoting properties. The benefits of a Brassica-based diet may be particularly expressed by eating sprouts, in which the glucosinolate content is higher than in mature vegetables. With this in mind, a first objective of this study was to evaluate the antioxidant properties of radish (Raphanus sativus L.) sprouts (Kaiware Daikon) extract (KDE), in which the glucosinolate glucoraphasatin (GRH), showing some antioxidant activity, is present at 10.5% w/w. The contribution of GRH to KDE's antioxidant activity was considered in two chemical assays (Trolox equivalent antioxidant capacity and Briggs-Rauscher methods). The total phenol assay by Folin-Ciocalteu reagent was performed to quantify the reducing capacity of KDE. Finally, on the basis of the putative choleretic properties of antioxidant plant extracts, the effect on the bile flow of KDE administration was investigated in an animal experimental model. The findings showed that KDE has antioxidant properties and significantly induced bile flow in rats administered 1.5 g/kg of body weight for 4 consecutive days.


Review article: antitumoural immunity in colorectal cancer - current and potential future implications in clinical practice.
Most of the current research in gastrointestinal oncology is focused on biology of cancer itself, but there is growing interest in the patient's immune system response and its relation with cancer cells. To review the impact of the antitumoural immune response on epidemiology, prognosis and treatment of colorectal cancer. Search of the literature published in English using the PubMed database. The role of the immune system in the antitumoural immunosurveillance is clearly supported by the increased incidence of colorectal cancer and adenomatous polyps in immunosuppressed patients. Moreover, the degree of infiltration of the tumours by the immune cells has been shown to be a strong prognostic factor of both disease recurrence and survival. The immune system plays an important role in the chemotherapy-induced cell death. New therapeutic strategies targeting the antitumoural immunity are being currently investigated with promising results. Better knowledge of antitumoural immune system can have a major impact on patients' management in daily clinical practice. Colorectal cancer screening is an important issue in immunosuppressed patients, and recommendations should be refined for selected high-risk patients. The use of an immune score to guide the therapeutic strategies in the adjuvant setting should be supported. Further and larger clinical trials are necessary to accelerate the development of innovative immune therapies.


Extracellular pH modulates block of both sodium and calcium channels by nicardipine.
Slowing of the recovery of the Na channel from local anesthetic block at low external pH has been well described. In contrast the Ca channel has been reported not to show such an effect. Because of the absence of this response, a two-site model for the interaction of Ca antagonists with the Ca channel has been proposed. We sought to determine whether these results were a consequence of utilizing the poorly lipid-soluble Ca antagonist diltiazem as the test drug. We have measured the time constants of recovery (tau r) of Na (INa) and Ca currents (ICa) recorded from rabbit atrial myocytes during control and exposure to the lipid-soluble Ca antagonist nicardipine as external pH was reduced from 7.8 to 6.9. In the absence of drug, tau r for INa decreased from 19 +/- 1.3 to 12.1 +/- 0.6 ms for the pH reduction. Similarly, tau r for ICa decreased from 53 +/- 7 to 33.6 +/- 7 ms. During exposure to nicardipine tau r for INa increased from 2.24 +/- 0.8 to 5.96 +/- 0.8 s as external pH was reduced. For ICa, tau r also increased from 1.43 +/- 0.55 to 2 +/- 0.32 s. For each channel type, the results are well explained by a single blocking site model with hydrophobic and hydrophilic pathways to a single membrane binding site as proposed by Hille (J. Gen. Physiol. 69: 497-517, 1977).


Serum metabolomics in animal models and human disease.
The aim of this study is to highlight some recent uses of serum metabolomics in human and animal studies. The main themes are the importance of understanding the underlying variation in human metabolism and the use of serum metabolomics in disease profiling. Several studies have attempted to use serum metabolomics to develop noninvasive biomarkers of disease and/or track the consequences of nutritional and genetic interventions. Many advances have been made with common changes being identified in ageing, the menopause and cancer but several problems of interpretation have emerged from these studies. These include the small sample sizes in most human studies and the differences between human and rodent metabolomes. However, a metabolic screen of over 1000 'healthy' humans (the Humsermet project) has highlighted many variables that may be used to refine the interpretation and design of previous and future human studies alike, in addition to data mining. Some common serum metabolome alterations have been identified but many inconsistencies remain. The construction of a human serum metabolome database should be informative in the design of future human and animal model studies.


Manipulating the experienced onset of intention after action execution.
Using transcranial magnetic stimulation (TMS), we have tested the time needed for the perceived onset of spontaneous motor intention to be fully determined. We found that TMS applied over the presupplementary motor area after the execution of a simple spontaneous action shifted the perceived onset of the motor intention backward in time, and shifted the perceived time of action execution forward in time. The size of the effect was similar regardless of whether TMS was applied immediately after the action or 200 msec after. The results of three control studies suggest that this effect is time-limited, specific to modality, and also specific to the anatomical site of stimulation. We conclude that the perceived onset of intention depends, at least in part, on neural activity that takes place after the execution of action. A model, which is based on the mechanism of cue integration under the presence of noise, is offered to explain the results. The implications for the conscious control of spontaneous actions are discussed.


An analysis of the genetic factors involved in testicular descent in a cohort of 14 male patients with anorchia.
Anorchia, or the "vanishing testis syndrome," is characterized by the absence of testis in a 46,XY individual with a male phenotype. The etiology is unknown; however, the familial occurrence of the disease and the association of this phenotype with 46,XY gonadal dysgenesis has led to the suggestion that genetic factors, which play a role in testicular determination, may be involved. Alternatively, exploratory laparoscopy has suggested that anorchia may be caused by a prenatal testicular vascular accident associated with torsion during testicular descent. We screened a cohort of 14 boys with bilateral anorchia for mutations in the Y chromosome-linked testis-determining gene SRY (sex-determining region, Y chromosome); in the gene necessary for correct testicular descent, INSL3; and in the gene of its receptor (LGR8). Mutations in the INSL3 gene and the LGR8 T222P mutation are known to cause cryptorchidism. We confirmed previous reports that mutations in the SRY gene are not associated with anorchia. Although a common polymorphism was identified in the INSL3 gene, no mutations were observed. The recurrent T222P mutation in the LGR8 gene was not found in any of the patients. These data show for the first time a lack of association between genetic factors necessary for correct testicular descent and anorchia.


Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia.
Contacts between endosomes and the endoplasmic reticulum (ER) promote endosomal tubule fission, but the mechanisms involved and consequences of tubule fission failure are incompletely understood. We found that interaction between the microtubule-severing enzyme spastin and the ESCRT protein IST1 at ER-endosome contacts drives endosomal tubule fission. Failure of fission caused defective sorting of mannose 6-phosphate receptor, with consequently disrupted lysosomal enzyme trafficking and abnormal lysosomal morphology, including in mouse primary neurons and human stem cell-derived neurons. Consistent with a role for ER-mediated endosomal tubule fission in lysosome function, similar lysosomal abnormalities were seen in cellular models lacking the WASH complex component strumpellin or the ER morphogen REEP1. Mutations in spastin, strumpellin, or REEP1 cause hereditary spastic paraplegia (HSP), a disease characterized by axonal degeneration. Our results implicate failure of the ER-endosome contact process in axonopathy and suggest that coupling of ER-mediated endosomal tubule fission to lysosome function links different classes of HSP proteins, previously considered functionally distinct, into a unifying pathway for axonal degeneration.


Evolution of opercle bone shape along a macrohabitat gradient: species identification using mtDNA and geometric morphometric analyses in neotropical sea catfishes (Ariidae).
Transitions between the marine and freshwater macrohabitat have occurred repeatedly in the evolution of teleost fishes. For example, ariid catfishes have moved from freshwater to marine environments, and vice versa. Opercles, a skeletal feature that has been shown to change during such transitions, were subjected to 2D geometric morphometric analyses in order to investigate evolutionary shape changes during habitat transition in ariid catfishes and to test the influence of habitat on shape changes. A mtDNA marker, which proved useful in previous studies, was used to verify species identities. It greatly improved the assignment of specimens to a species, which are difficult to assign by morphology alone. The application of a mtDNA marker confirmed the occurrence of Notarius biffi in Central America, South of El Salvador. Molecular identification together with principal component analysis (PCA) and further morphological inspection of neurocrania indicated the existence of a cryptic species within Bagre pinnimaculatus. Principal component (PC) scores of individual specimens clustered in morphospace by genus rather than by habitat. Strong phylogenetic structure was detected using a permutation test of PC scores of species means on a phylogenetic tree. Calculation of Pagel's λ suggested that opercle shape evolved according to a Brownian model of evolution. Yet canonical variate analysis (CVA) conducted on the habitat groups showed significant differences in opercle shapes among freshwater and marine species. Overall, opercle shape in tropical American Ariidae appears to be phylogenetically constrained. This verifies the application of opercle shape as a taxonomic tool for species identification in fossil ariid catfishes. At the same time, adaptation to freshwater habitats shows characteristic opercle shape trajectories in ariid catfishes, which might be used to detect habitat preferences in fossils.


Calcium-sensing receptor modulates cell adhesion and migration via integrins.
The calcium-sensing receptor (CaSR) is a family C G protein-coupled receptor that is activated by elevated levels of extracellular divalent cations. The CaSR couples to members of the G(q) family of G proteins, and in the endocrine system this receptor is instrumental in regulating the release of parathyroid hormone from the parathyroid gland and calcitonin from thyroid cells. Here, we demonstrate that in medullary thyroid carcinoma cells, the CaSR promotes cellular adhesion and migration via coupling to members of the integrin family of extracellular matrix-binding proteins. Immunopurification and mass spectrometry, co-immunoprecipitation, and co-localization studies showed that the CaSR and β1-containing integrins are components of a macromolecular protein complex. In fibronectin-based cell adhesion and migration assays, the CaSR-positive allosteric modulator NPS R-568 induced a concentration-dependent increase in cell adhesion and migration; both of these effects were blocked by a specific CaSR-negative allosteric modulator. These effects were mediated by integrins because they were blocked by a peptide inhibitor of integrin binding to fibronectin and β1 knockdown experiments. An analysis of intracellular signaling pathways revealed a key role for CaSR-induced phospholipase C activation and the release of intracellular calcium. These results demonstrate for the first time that an ion-sensing G protein-coupled receptor functionally couples to the integrins and, in conjunction with intracellular calcium release, promotes cellular adhesion and migration in tumor cells. The significance of this interaction is further highlighted by studies implicating the CaSR in cancer metastasis, axonal growth, and stem cell attachment, functions that rely on integrin-mediated cell adhesion.


Mobile device camera design with Q-type polynomials to achieve higher production yield.
The camera lenses that are built into the current generation of mobile devices are extremely stressed by the excessively tight packaging requirements, particularly the length. As a result, the aspheric departures and slopes on the lens surfaces, when designed with conventional power series based aspheres, are well beyond those encountered in most optical systems. When the as-manufactured performance is considered, the excessive aspheric slopes result in unusually high sensitivity to tilt and decenter and even despace resulting in unusually low manufacturing yield. Q(bfs) polynomials, a new formulation for nonspherical optical surfaces introduced by Forbes, not only build on orthogonal polynomials, but their unique normalization provides direct access to the RMS slope of the aspheric departure during optimization. Using surface shapes with this description in optimization results in equivalent performance with reduced alignment sensitivity and higher yield. As an additional approach to increasing yield, mechanically imposed external pivot points, introduced by Bottema, can be used as a design technique to further reduce alignment sensitivity and increase yield. In this paper, the Q-type polynomials and external pivot points were applied to a mobile device camera lens designed using an active RMS slope constraint that was then compared to a design developed using conventional power series surface descriptions. Results show that slope constrained Q-type polynomial description together with external pivot points lead directly to solutions with significantly higher manufacturing yield.


Physiological melatonin inhibition of human breast cancer cell growth in vitro: evidence for a glutathione-mediated pathway.
Melatonin, the chief hormone secreted by the pineal gland, has been previously shown to inhibit human breast cancer cell growth at the physiological concentration of 1 nM in vitro. In this study, using the estrogen receptor (ER)-positive human breast tumor cell line MCF-7, we have shown that 10 microM L-buthionine-[S,R]-sulfoximine (L-BSO), an inhibitor of gamma-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione synthesis), blocks the oncostatic action of 1 nM melatonin over a 5-day incubation, indicating that glutathione is required for melatonin action. The result was repeated with ZR75-1 cells, suggesting that the glutathione requirement is a general phenomenon among ER+ breast cancer cells. Addition of exogenous glutathione (1 microM) to L-BSO-treated groups restored the melatonin response in both cell lines. Further demonstration of the importance of glutathione was shown using the ER- breast tumor cell line HS578T, which is normally unresponsive to melatonin. Growth in this cell line was inhibited in the presence of 1 microM ethacrynic acid (an inhibitor of glutathione S-transferase) plus 1 nM melatonin, and this effect was blocked with 10 microM L-BSO. We also observed a steady decrease of intracellular glutathione in MCF-7 cells over a 5-day incubation, suggesting that these cells metabolize glutathione differently than do normal cells.


Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation.
Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect. To evaluate the efficacy and safety of parenteral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation. A comprehensive search included (1) an electronic search (February 2010) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2010, MEDLINE, EMBASE and ISI the Web of Science; (2) handsearch of conference proceedings; (3) checking of references of included studies; and (4) use of the 'related citation' feature in PubMed. Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in patients with cancer but no therapeutic or prophylactic indication for anticoagulation. Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic thromboembolism, major bleeding, minor bleeding and quality of life (QoL). Of 8187 identified citations, nine RCTs enrolling 2857 patients fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, the effect of heparin therapy on mortality was not statistically significant at 12 months (risk ratio (RR) 0.93; 95% CI 0.85 to 1.02) but it was statistically significant at 24 months (RR 0.92; 95% CI 0.88 to 0.97). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.55; 95% CI 0.37 to 0.82). There were no statistically significant effects on major bleeding (RR 1.30; 95% CI 0.59 to 2.88), minor bleeding (RR 1.05; 95% 0.75 to 1.46) or QoL. The quality of evidence was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for QoL. Heparin was associated with a significant reduction of death at 24 months but not 12 months. It was also associated with a reduction in venous thromboembolism but based on the RCTs in this review it had no significant effect on major bleeding, minor bleeding or QoL. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides and integrate the patient's values and preferences.


The Proportion of Lower Limb Running Injuries by Gender, Anatomical Location and Specific Pathology: A Systematic Review.
Running is associated with a higher risk of overuse injury than other forms of aerobic exercise such as walking, swimming and cycling. An accurate description of the proportion of running injuries per anatomical location and where possible, per specific pathology, for both genders is required. The aim of this review was to determine the proportion of lower limb running injuries by anatomical location and by specific pathology in male and female runners (≥800m - ≤ marathon). The preferred reporting items for systematic reviews and meta-analyses guidelines were followed for this review. A literature search was performed with no restriction on publication year in Web of Science, Scopus, Sport-Discus, PubMed, and CINAHL up to July 2017. Retrospective, cross-sectional, prospective and randomised-controlled studies which surveyed injury data in runners were included. 36 studies were included to report the overall proportion of injury per anatomical location. The overall proportion of injury by specific pathology was reported from 11 studies. The knee (28%), ankle-foot (26%) and shank (16%) accounted for the highest proportion of injury in male and female runners, although the proportion of knee injury was greater in women (40% vs. 31%). Relative to women, men had a greater proportion of ankle-foot (26% vs. 19%) and shank (21% vs. 16%) injuries. Patellofemoral pain syndrome (PFPS; 17%), Achilles tendinopathy (AT; 10%) and medial tibial stress syndrome (MTS; 8%) accounted for the highest proportion of specific pathologies recorded overall. There was insufficient data to sub-divide specific pathology between genders. The predominate injury in female runners is to the knee. Male runners have a more even distribution of injury between the knee, shank and ankle-foot complex. There are several methodological issues, which limit the interpretation of epidemiological data in running injury.


GLUT1 expression patterns in different Hodgkin lymphoma subtypes and progressively transformed germinal centers.
Increased glycolytic activity is a hallmark of cancer, allowing staging and restaging with 18F-fluorodeoxyglucose-positron-emission-tomography (PET). Since interim-PET is an important prognostic tool in Hodgkin lymphoma (HL), the aim of this study was to investigate the expression of proteins involved in the regulation of glucose metabolism in the different HL subtypes and their impact on clinical outcome. Lymph node biopsies from 54 HL cases and reactive lymphoid tissue were stained for glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA) and lactate exporter proteins MCT1 and MCT4. In a second series, samples from additional 153 HL cases with available clinical data were stained for GLUT1 and LDHA. Membrane bound GLUT1 expression was frequently observed in the tumor cells of HL (49% of all cases) but showed a broad variety between the different Hodgkin lymphoma subtypes: Nodular sclerosing HL subtype displayed a membrane bound GLUT1 expression in the Hodgkin-and Reed-Sternberg cells in 56% of the cases. However, membrane bound GLUT1 expression was more rarely observed in tumor cells of lymphocyte rich classical HL subtype (30%) or nodular lymphocyte predominant HL subtype (15%). Interestingly, in both of these lymphocyte rich HL subtypes as well as in progressively transformed germinal centers, reactive B cells displayed strong expression of GLUT1. LDHA, acting downstream of glycolysis, was also expressed in 44% of all cases. We evaluated the prognostic value of different GLUT1 and LDHA expression patterns; however, no significant differences in progression free or overall survival were found between patients exhibiting different GLUT1 or LDHA expression patterns. There was no correlation between GLUT1 expression in HRS cells and PET standard uptake values. In a large number of cases, HRS cells in classical HL express high levels of GLUT1 and LDHA indicating glycolytic activity in the tumor cells. Although interim-PET is an important prognostic tool, a predictive value of GLUT1 or LDHA staining of the primary diagnostic biopsy could not be demonstrated. However, we observed GLUT1 expression in progressively transformed germinal centers and hyperplastic follicles, explaining false positive results in PET. Therefore, PET findings suggestive of HL relapse should always be confirmed by histology.


Bioenergy grass feedstock: current options and prospects for trait improvement using emerging genetic, genomic, and systems biology toolkits.
For lignocellulosic bioenergy to become a viable alternative to traditional energy production methods, rapid increases in conversion efficiency and biomass yield must be achieved. Increased productivity in bioenergy production can be achieved through concomitant gains in processing efficiency as well as genetic improvement of feedstock that have the potential for bioenergy production at an industrial scale. The purpose of this review is to explore the genetic and genomic resource landscape for the improvement of a specific bioenergy feedstock group, the C4 bioenergy grasses. First, bioenergy grass feedstock traits relevant to biochemical conversion are examined. Then we outline genetic resources available bioenergy grasses for mapping bioenergy traits to DNA markers and genes. This is followed by a discussion of genomic tools and how they can be applied to understanding bioenergy grass feedstock trait genetic mechanisms leading to further improvement opportunities.


Factor XIII: novel structural and functional aspects.
Factor (F)XIII is a protransglutaminase that, in addition to maintaining hemostasis, has multiple plasmatic and intracellular functions. Its plasmatic form (pFXIII) is a tetramer of two potentially active A (FXIII-A) and two inhibitory/carrier B (FXIII-B) subunits, whereas its cellular form (cFXIII) is a dimer of FXIII-A. FXIII-A belongs to the family of transglutaminases (TGs), which show modest similarity in the primary structure, but a high degree of conservatism in their domain and sub-domain secondary structure. FXIII-A consists of an activation peptide, a β-sandwich, a catalytic and two β-barrel domains. FXIII-B is a glycoprotein consisting of 10 repetitive sushi domains each held together by two internal disulfide bonds. The structural elements of FXIII-A involved in the interaction with FXIII-B have not been elucidated; in FXIII-B the first sushi domain seems important for complex formation. In the circulation pFXIII is bound to the fibrinogen γ'-chain through its B subunit. In the process of pFXIII activation first thrombin cleaves off the activation peptide from FXIII-A, then in the presence of Ca(2+) FXIII-B dissociates and FXIII-A becomes transformed into an active transglutaminase (FXIIIa). The activation is highly accelerated by the presence of fibrin(ogen). cFXIII does not require proteolysis for intracellular activation. The three-dimensional structure of FXIIIa has not been resolved. Based on analogies with transglutaminase-2, a three-dimensional structure of FXIIIa was developed by molecular modeling, which shows good agreement with the drastic structural changes demonstrated by biochemical studies. The structural requirements for enzyme-substrate interaction and for transglutaminase activity are also reviewed.


Prevalence of Healthy Behaviors among Cancer Survivors in the United States: How Far Have We Come?
The 16.9 million cancer survivors in the United States are at increased risk for comorbidities and recurrence. However, this risk may be attenuated by a healthy lifestyle. This study describes health behaviors by cancer history to inform behavior change priorities. We analyzed 2013-2017 data from the National Health Interview Survey. There were 164,692 adults, of whom 12,648 reported a cancer history. We calculated prevalence of smoking, physical activity, alcohol consumption, body mass index (BMI), and sleep duration by cancer history, age, and cancer site. We conducted logistic regression to determine odds of meeting lifestyle recommendations by cancer history. Overall, those with a cancer history were less likely to report current smoking (14.1% vs. 16.8%) and moderate/heavy drinking (18.8% vs. 21.9%) than those without a cancer history. However, a lower percentage of cancer survivors met physical activity guidelines (14.2% vs. 21.1%) or reported a healthy BMI (31.6% vs. 34.7%) compared with those without a cancer history. Cancer survivors were more likely to report excessive sleep (6.8% vs. 3.6%). In adjusted logistic regression, survivors were more likely to meet recommendations on smoking, physical activity, and BMI but were less likely to meet alcohol recommendations; meeting sleep recommendations did not differ by cancer history. While cancer survivors had lower prevalence of smoking and moderate/heavy drinking, they also had lower prevalence of physical activity and healthy BMI, and reported longer sleep duration. Regression analyses suggested survivors only showed poorer behaviors for alcohol. Targeted health promotion interventions among cancer survivors are needed.


Key driver genes as potential therapeutic targets in renal allograft rejection.
Acute rejection (AR) in renal transplantation is an established risk factor for reduced allograft survival. Molecules with regulatory control among immune pathways of AR that are inadequately suppressed, despite standard-of-care immunosuppression, could serve as important targets for therapeutic manipulation to prevent rejection. Here, an integrative, network-based computational strategy incorporating gene expression and genotype data of human renal allograft biopsy tissue was applied, to identify the master regulators - the key driver genes (KDGs) - within dysregulated AR pathways. A 982-meta-gene signature with differential expression in AR versus non-AR was identified from a meta-analysis of microarray data from 735 human kidney allograft biopsy samples across 7 data sets. Fourteen KDGs were derived from this signature. Interrogation of 2 publicly available databases identified compounds with predicted efficacy against individual KDGs or a key driver-based gene set, respectively, which could be repurposed for AR prevention. Minocycline, a tetracycline antibiotic, was chosen for experimental validation in a murine cardiac allograft model of AR. Minocycline attenuated the inflammatory profile of AR compared with controls and when coadministered with immunosuppression prolonged graft survival. This study demonstrates that a network-based strategy, using expression and genotype data to predict KDGs, assists target prioritization for therapeutics in renal allograft rejection.


Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can spread rapidly within skilled nursing facilities. After identification of a case of Covid-19 in a skilled nursing facility, we assessed transmission and evaluated the adequacy of symptom-based screening to identify infections in residents. We conducted two serial point-prevalence surveys, 1 week apart, in which assenting residents of the facility underwent nasopharyngeal and oropharyngeal testing for SARS-CoV-2, including real-time reverse-transcriptase polymerase chain reaction (rRT-PCR), viral culture, and sequencing. Symptoms that had been present during the preceding 14 days were recorded. Asymptomatic residents who tested positive were reassessed 7 days later. Residents with SARS-CoV-2 infection were categorized as symptomatic with typical symptoms (fever, cough, or shortness of breath), symptomatic with only atypical symptoms, presymptomatic, or asymptomatic. Twenty-three days after the first positive test result in a resident at this skilled nursing facility, 57 of 89 residents (64%) tested positive for SARS-CoV-2. Among 76 residents who participated in point-prevalence surveys, 48 (63%) tested positive. Of these 48 residents, 27 (56%) were asymptomatic at the time of testing; 24 subsequently developed symptoms (median time to onset, 4 days). Samples from these 24 presymptomatic residents had a median rRT-PCR cycle threshold value of 23.1, and viable virus was recovered from 17 residents. As of April 3, of the 57 residents with SARS-CoV-2 infection, 11 had been hospitalized (3 in the intensive care unit) and 15 had died (mortality, 26%). Of the 34 residents whose specimens were sequenced, 27 (79%) had sequences that fit into two clusters with a difference of one nucleotide. Rapid and widespread transmission of SARS-CoV-2 was demonstrated in this skilled nursing facility. More than half of residents with positive test results were asymptomatic at the time of testing and most likely contributed to transmission. Infection-control strategies focused solely on symptomatic residents were not sufficient to prevent transmission after SARS-CoV-2 introduction into this facility.


A ubiquitin replacement strategy in human cells reveals distinct mechanisms of IKK activation by TNFalpha and IL-1beta.
Lysine-63 (K63)-linked polyubiquitination has emerged as a mechanism regulating diverse cellular functions, including activation of the protein kinase IKK in the NF-kappaB pathways. However, genetic evidence for a key role of K63 polyubiquitination in IKK activation is lacking. Here, we devise a tetracycline-inducible RNAi strategy to replace endogenous ubiquitin with a K63R mutant in a human cell line. We demonstrate that K63 of ubiquitin and the catalytic activity of Ubc13, an E2 that catalyzes K63 polyubiquitination, are required for IKK activation by IL-1beta, but surprisingly, not by TNFalpha. We further show that IKK activation by TNFalpha requires Ubc5, which functions with the E3 cIAP1 to catalyze polyubiquitination of RIP1 not restricted to K63 of ubiquitin. These results indicate that distinct ubiquitin-dependent mechanisms are employed for IKK activation by different pathways. The ubiquitin replacement methodology described here provides a means to investigate the function of polyubiquitin topology in various cellular processes.


Effects of Bixa orellana L. seeds on hyperlipidemia.
Bixa orellana L., urucum, or urucu, a native tropical tree of Central and South American rain forests is used to treat various diseases in popular medicine. In Ceará, Northeast of Brazil, the seeds of urucum have been used for the treatment of high lipid blood levels. The present study investigated the effects of the aqueous extract from Bixa orellana seeds (AEBO) in mice with hyperlipidemia induced by tyloxapol, fructose and ethanol. In hyperlipidemia induced by Triton WR1339, 400 and 800 mg/kg AEBO reduced triglycerides (TG) serum levels at 24 h and 48 h. In the study of hypertriglyceridemia induced by fructose, AEBO in doses of 400 mg/kg and 800 mg/kg reduced TG levels by 48.2% and 48.7%, respectively. Finally, the ethanol experimental model with 400 mg/kg AEBO promoted a reduction of 33.6% of TG levels, while the 800 mg/kg concentration reduced hypertriglyceridemia in 62.2%. In conclusion, the aqueous extract of the seeds of Bixa orellana was capable of reversing the hypertriglyceridemia induced by Triton, fructose and ethanol, demonstrating a hypolipidemic effect. However, further studies are necessary to discover the precise mechanism of action.


Large-scale structure and matter in the Universe.
This paper summarizes the physical mechanisms that encode the type and quantity of cosmological matter in the properties of large-scale structure, and reviews the application of such tests to current datasets. The key lengths of the horizon size at matter-radiation equality and at last scattering determine the total matter density and its ratio to the relativistic density; acoustic oscillations can diagnose whether the matter is collisionless, and small-scale structure or its absence can limit the mass of any dark-matter relic particle. The most stringent constraints come from combining data on present-day galaxy clustering with data on CMB anisotropies. Such an analysis breaks the degeneracies inherent in either dataset alone, and proves that the Universe is very close to flat. The matter content is accurately consistent with pure cold dark matter, with ca. 25% of the critical density, and fluctuations that are scalar only, adiabatic and scale invariant. It is demonstrated that these conclusions cannot be evaded by adjusting either the equation of state of the vacuum, or the total relativistic density.


Trends for the past 10 years and international comparisons of the structure of Korean radiation oncology.
Study aims include determination of nationwide structural characteristics of radiation oncology facilities, types of radiation therapy equipment, availability of human resources and trends and comparisons with previous surveys. An annual nationwide survey was conducted to collect the statistics of infrastructure since 1997. All requested questionnaires have been identical for 10 years. The questionnaires included status on basic radiation therapy facilities, human resources and radiation therapy equipment. Journal and statistical data reviews were performed to evaluate the structure of other countries. Radiation oncology facilities have steadily increased for 10 years and reached 60 sites in 2006. Also a steady increase of 1.5 times for linear accelerators, 5.8 times for computed tomography simulators and 3.0 times for radiation treatment planning systems was noted. Meanwhile, cobalt-60 teletherapy units and hyperthermia equipment had steadily deceased for 10 years. The number of human resources has steadily increased for the past 10 years, especially for radiation therapy technologists. However, radiation therapy equipment and human resources per population are relatively low compared with advanced countries. This study will assist preparation of the administrative planning policy of radiation oncology and should be useful to indicate the direction of future development and educational training programs in Korea and possibly in other countries.


ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.
High-throughput sequencing platforms are generating massive amounts of genetic variation data for diverse genomes, but it remains a challenge to pinpoint a small subset of functionally important variants. To fill these unmet needs, we developed the ANNOVAR tool to annotate single nucleotide variants (SNVs) and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP. ANNOVAR can utilize annotation databases from the UCSC Genome Browser or any annotation data set conforming to Generic Feature Format version 3 (GFF3). We also illustrate a 'variants reduction' protocol on 4.7 million SNVs and indels from a human genome, including two causal mutations for Miller syndrome, a rare recessive disease. Through a stepwise procedure, we excluded variants that are unlikely to be causal, and identified 20 candidate genes including the causal gene. Using a desktop computer, ANNOVAR requires ∼4 min to perform gene-based annotation and ∼15 min to perform variants reduction on 4.7 million variants, making it practical to handle hundreds of human genomes in a day. ANNOVAR is freely available at http://www.openbioinformatics.org/annovar/.


Effects of temperature on transcriptome and cuticular hydrocarbon expression in ecologically differentiated populations of desert Drosophila.
We assessed the effects of temperature differences on gene expression using whole-transcriptome microarrays and cuticular hydrocarbon variation in populations of cactophilic Drosophila mojavensis. Four populations from Baja California and mainland Mexico and Arizona were each reared on two different host cacti, reared to sexual maturity on laboratory media, and adults were exposed for 12 hr to 15, 25, or 35°C. Temperature differences influenced the expression of 3,294 genes, while population differences and host plants affected >2,400 each in adult flies. Enriched, functionally related groups of genes whose expression changed at high temperatures included heat response genes, as well as genes affecting chromatin structure. Gene expression differences between mainland and peninsular populations included genes involved in metabolism of secondary compounds, mitochondrial activity, and tRNA synthases. Flies reared on the ancestral host plant, pitaya agria cactus, showed upregulation of genes involved in metabolism, while flies reared on organ pipe cactus had higher expression of DNA repair and chromatin remodeling genes. Population × environment (G × E) interactions had widespread effects on the transcriptome where population × temperature interactions affected the expression of >5,000 orthologs, and there were >4,000 orthologs that showed temperature × host plant interactions. Adults exposed to 35°C had lower amounts of most cuticular hydrocarbons than those exposed to 15 or 25°C, including abundant unsaturated alkadienes. For insects adapted to different host plants and climatic regimes, our results suggest that temperature shifts associated with climate change have large and significant effects on transcriptomes of genetically differentiated natural populations.


Physico-chemical properties of a novel (-)-hydroxycitric acid extract and its effect on body weight, selected organ weights, hepatic lipid peroxidation and DNA fragmentation, hematology and clinical chemistry, and histopathological changes over a period of 90 days.
Garcinia cambogia-derived (-)-hydroxycitric acid (HCA) is a popular and natural supplement for weight management. HCA is a competitive inhibitor of the enzyme ATP citrate lyase, which catalyzes the conversion of citrate and coenzyme A to oxaloacetate and acetyl coenzyme A (acetyl CoA) in the cytosol. Acetyl CoA is used in the synthesis of fatty acids, cholesterol and triglycerides, and in the synthesis of acetylcholine in the central nervous system. Studies have demonstrated the efficacy of a novel 60% calcium-potassium salt of HCA derived from Garcinia cambogia (HCA-SX, Super CitriMax) in weight management. Results have shown that HCA-SX promotes fat oxidation, enhances serotonin release and availability in the brain cortex, normalizes lipid profiles, and lowers serum leptin levels in obese subjects. Acute oral, acute dermal, primary dermal irritation and primary eye irritation toxicity, as well as Ames bacterial reverse mutation studies and mouse lymphoma tests have demonstrated the safety of HCA-SX. However, no detailed long-term safety of HCA-SX or any other HCA extract has been previously assessed. We evaluated the dose- and time-dependent effects of HCA-SX in Sprague-Dawley rats on body weight, selected organ weights, hepatic lipid peroxidation and DNA fragmentation, hematology and clinical chemistry over a period of 90 days. Furthermore, a 90-day histopathological evaluation was conducted. The animals were treated with 0, 0.2, 2.0 and 5.0% HCA-SX of feed intake and were sacrificed on 30, 60 or 90 days of treatment. The body weight and selected organ weights were assessed and correlated as a % of body weight and brain weight at 90 days of treatment. A significant reduction in body weight was observed in treated rats as compared to control animals. An advancing age-induced marginal increase in hepatic lipid peroxidation was observed in both male and female rats, while no such difference in hepatic DNA fragmentation was observed as compared to the control animals. Furthermore, selected organ weights individually and as a % of body weight and brain weight at 90 days of treatment exhibited no significant difference between the groups. No difference was observed in hematology and clinical chemistry or the histopathological evaluation. Taken together, these results show that 90 day treatment of HCA-SX results in a reduction in body weight, and does not cause any changes in major organs or in hematology, clinical chemistry, and histopathology.


GIS-based niche modeling for mapping species' habitat.
Ecological "niche modeling" using presence-only locality data and large-scale environmental variables provides a powerful tool for identifying and mapping suitable habitat for species over large spatial extents. We describe a niche modeling approach that identifies a minimum (rather than an optimum) set of basic habitat requirements for a species, based on the assumption that constant environmental relationships in a species' distribution (i.e., variables that maintain a consistent value where the species occurs) are most likely to be associated with limiting factors. Environmental variables that take on a wide range of values where a species occurs are less informative because they do not limit a species' distribution, at least over the range of variation sampled. This approach is operationalized by partitioning Mahalanobis D2 (standardized difference between values of a set of environmental variables for any point and mean values for those same variables calculated from all points at which a species was detected) into independent components. The smallest of these components represents the linear combination of variables with minimum variance; increasingly larger components represent larger variances and are increasingly less limiting. We illustrate this approach using the California Gnatcatcher (Polioptila californica Brewster) and provide SAS code to implement it.


Phosphatase inhibitor-2 balances protein phosphatase 1 and aurora B kinase for chromosome segregation and cytokinesis in human retinal epithelial cells.
Mitosis in Saccharomyces cerevisiae depends on IPL1 kinase, which genetically interacts with GLC8. The metazoan homologue of GLC8 is inhibitor-2 (I-2), but its function is not understood. We found endogenous and ectopic I-2 localized to the spindle, midzone, and midbody of mitotic human epithelial ARPE-19 cells. Knockdown of I-2 by RNA interference produced multinucleated cells, with supernumerary centrosomes, multipolar spindles and lagging chromosomes during anaphase. These defects did not involve changes in levels of protein phosphatase-1 (PP1), and the multinuclear phenotype was rescued by overexpression of I-2. Appearance of multiple nuclei and supernumerary centrosomes required progression through the cell cycle and I-2 knockdown cells failed cytokinesis, as observed by time-lapse microscopy. Inhibition of Aurora B by hesperadin produced multinucleated cells and reduced H3S10 phosphorylation. I-2 knockdown enhanced this latter effect. Partial knockdown of PP1Calpha prevented multiple nuclei caused by either knockdown of I-2 or treatment with hesperadin. Expression of enhanced green fluorescent protein-I-2 or hemagglutinin-I-2 made cells resistant to hesperadin. We propose that I-2 acts to enhance Aurora B by inhibiting specific PP1 holoenzymes that dephosphorylate Aurora B substrates necessary for chromosome segregation and cytokinesis. Conserved together throughout eukaryotic evolution, I-2, PP1 and Aurora B function interdependently during mitosis.


Estrogenic suppression of binge-like eating elicited by cyclic food restriction and frustrative-nonreward stress in female rats.
Because binge eating and emotional eating vary through the menstrual cycle in human females, we investigated cyclic changes in binge-like eating in female rats and their control by estrogens. Binge-like eating was elicited by three cycles of 4 days of food restriction and 4 days of free feeding followed by a single frustrative nonreward-stress episode (15 min visual and olfactory exposure to a familiar palatable food) immediately before presentation of the palatable food. Intact rats showed binge-like eating during the diestrous and proestrous phases of the ovarian cycle, but not during the estrous (periovulatory) phase. Ovariectomized (OVX) rats not treated with estradiol (E2) displayed binge-like eating, whereas E2-treated OVX rats did not. The procedure did not increase signs of anxiety in an open-field test. OVX rats not treated with E2 that were subjected to food restriction and sacrificed immediately after frustrative nonreward had increased numbers of cells expressing phosphorylated extracellular signal-regulated kinases (ERK) in the central nucleus of the amygdala (CeA), paraventricular nucleus of hypothalamus (PVN), and dorsal and ventral bed nuclei of the stria terminalis (BNST) compared with nonrestricted or E2-treated rats. These data suggest that this female rat model is appropriate for mechanistic studies of some aspects of menstrual-cycle effects on emotional and binge eating in human females, that anxiety is not a sufficient cause of binge-like eating, and that the PVN, CeA, and BNST may contribute to information processing underlying binge-like eating.


Anti-stress, anti-HIV and vitamin C-synergized radical scavenging activity of mulberry juice fractions.
Anti-stress and anti-HIV activity of mulberry juice were separated by centrifugation. The anti-stress activity was enriched in the supernatant fraction whereas the anti-HIV activity in the precipitate fraction. Oral administration of the supernatant fraction significantly reduced the elevated plasma level of lipid peroxide in mice loaded with water immersion restraint stress. The kinetic study revealed that the anti-stress activity was maintained for 4 hours after cessation of the administration of mulberry juice. The lignin fraction in the precipitate fraction scavenged superoxide and hydroxyl radicals more efficiently than other fractions, in a synergistic fashion with sodium ascorbate. Anti-HIV activity of mulberry juice was concentrated in the lignin fraction, whereas blueberry juice, which has no precipitating fibrous materials, did not show anti-HIV activity. The present study suggests the functionality of mulberry juice as an alternative medicine.


Highly efficient and selective isolation of rare tumor cells using a microfluidic chip with wavy-herringbone micro-patterned surfaces.
Circulating tumor cells (CTCs) in peripheral blood have been recognized as a general biomarker for diagnosing cancer and providing guidance for personalized treatments. Yet due to their rarity, the challenge for their clinical utility lies in the efficient isolation while avoiding the capture of other non-targeted white blood cells (WBCs). In this paper, a wavy-herringbone (HB) microfluidic chip coated with antibody directly against epithelial cell adhesion molecule (anti-EpCAM) was developed for highly efficient and selective isolation of tumor cells from tumor cell-spiked whole blood samples. By extending the concept of the hallmark HB-Chip in the literature, the wavy-HB chip not only achieves high capture efficiency (up to 85.0%) by micro-vortexes induced by HB structures, but also achieves high purity (up to 39.4%) due to the smooth wavy microstructures. These smooth wavy-HB structures eliminate the ultra-low shear rate regions in the traditional grooved-HB structures that lead to non-specific trapping of cells. Compared with the grooved-HB chip with sharp corners, the wavy-HB chip shows significantly higher purity while maintaining similarly high capture efficiency. Furthermore, the wavy-HB chip has up to 11% higher captured cell viability over the grooved-HB chip. The distributions of tumor cells and WBCs along the grooves and waves are investigated to help understand the mechanisms behind the better performance of the wavy-HB chip. The wavy-HB chip may serve as a promising platform for CTC capture and cancer diagnosis.


Chlamydia Outer Protein (Cop) B from Chlamydia pneumoniae possesses characteristic features of a type III secretion (T3S) translocator protein.
Chlamydia spp. are believed to use a conserved virulence factor called type III secretion (T3S) to facilitate the delivery of effector proteins from the bacterial pathogen to the host cell. Important early effector proteins of the type III secretion system (T3SS) are a class of proteins called the translocators. The translocator proteins insert into the host cell membrane to form a pore, allowing the injectisome to dock onto the host cell to facilitate translocation of effectors. CopB is a predicted hydrophobic translocator protein within the chlamydial T3SS. In this study, we identified a novel interaction between the hydrophobic translocator, CopB, and the putative filament protein, CdsF. Furthermore, we identified a conserved PxLxxP motif in CopB (amino acid residues 166-171), which is required for interaction with its cognate chaperone, LcrH_1. Using a synthetic peptide derived from the chaperone binding motif of CopB, we were able to block the LcrH_1 interaction with either CopB or CopD; this CopB peptide was capable of inhibiting C. pneumoniae infection of HeLa cells at micromolar concentrations. An antibody raised against the N-terminus of CopB was able to inhibit C. pneumoniae infection of HeLa cells. The inhibition of the LcrH_1:CopB interaction with a cognate peptide and subsequent inhibition of host cell infection provides strong evidence that T3S is an essential virulence factor for chlamydial infection and pathogenesis. Together, these results support that CopB plays the role of a hydrophobic translocator.


Simeprevir or telaprevir with peginterferon and ribavirin for recurrent hepatitis C after living-donor liver transplantation: A Japanese multicenter experience.
This study aimed to clarify the efficacy and safety of simeprevir, a second-generation NS3/4A inhibitor, with peginterferon and ribavirin for recurrent hepatitis C after liver transplantation. A retrospective cohort study of living-donor liver transplant recipients with recurrent hepatitis C with the hepatitis C virus genotype 1 treated with either simeprevir- or telaprevir-based triple therapy was carried out at eight Japanese liver transplant centers. Simeprevir- and telaprevir-based triple therapies were given to 79 and 36 patients, respectively. Of the 79 patients treated with simeprevir-based triple therapy, 44 (56%) achieved sustained virological response 12 weeks (SVR12) after treatment ended, and there was no significant difference in the SVR12 between the simeprevir- and telaprevir-based triple therapy groups (69%). The rates of adverse events were not significantly different between the simeprevir- and telaprevir-based triple therapy groups, although the rate of patients who received blood cell transfusion and erythropoietin due to anemia and had renal insufficiency were significantly higher in the telaprevir group than in the simeprevir group. Three baseline factors, the presence of prior dual therapy with peginterferon and ribavirin (P = 0.001), a non-responder to the prior dual therapy (P < 0.001), and male sex (P = 0.040), were identified as significant predictive factors for non-SVR with simeprevir-based triple therapy. Simeprevir-based triple therapy for recurrent hepatitis C after living-donor liver transplantation resulted in a high SVR rate and good tolerability, especially in treatment-naïve patients.


Local activation of yeast ASH1 mRNA translation through phosphorylation of Khd1p by the casein kinase Yck1p.
In S. cerevisiae, the ASH1 mRNA is localized at the bud tip of late-anaphase cells, resulting in the exclusive sorting of Ash1p to the daughter cell nucleus. While the mechanism behind the localization of this transcript has been well studied, the regulation of its translation is still poorly understood. We now report that the RNA binding protein Khd1 interacts with the ASH1 mRNA localization element E1 and with the C-terminal domain of eIF4G1 to regulate the translation of this transcript. Khd1p reduces translation initiation on the ASH1 mRNA and diminishes Ash1p leakage into the mother cell nucleus. Furthermore, we show that the casein kinase Yck1p phosphorylates Khd1p at the plasma membrane, disrupting the Khd1p-RNA complex and releasing its translational repression on the ASH1 mRNA. This study reveals how, by linking mRNA sorting and translational activation, Khd1p and Yck1p regulate the spatiotemporal expression of a cell fate determinant.


Low-frequency positive-pressure ventilation with extracorporeal CO2 removal in severe acute respiratory failure.
Forty-three patients were entered in an uncontrolled study designed to evaluate extracorporeal membrane lung support in severe acute respiratory failure of parenchymal origin. Most of the metabolic carbon dioxide production was cleared through a low-flow venovenous bypass. To avoid lung injury from conventional mechanical ventilation, the lungs were kept "at rest" (three to five breaths per minute) at a low peak airway pressure of 35 to 45 cm H2O (3.4 to 4.4 kPa). The entry criteria were based on gas exchange under standard ventilatory conditions (expected mortality rate, greater than 90%). Lung function improved in thirty-one patients (72.8%), and 21 patients (48.8%) eventually survived. The mean time on bypass for the survivors was 5.4 +/- 3.5 days. Improvement in lung function, when present, always occurred within 48 hours. Blood loss averaged 1800 +/- 850 mL/d. No major technical accidents occurred in more than 8000 hours of perfusion. Extracorporeal carbon dioxide removal with low-frequency ventilation proved a safe technique, and we suggest it as a valuable tool and an alternative to treating severe acute respiratory failure by conventional means.


Voltage pulses change neural interface properties and improve unit recordings with chronically implanted microelectrodes.
Current neuroprosthetic systems based on electro-physiological recording have an extended, yet finite working lifetime. Some posited lifetime-extension solutions involve improving device biocompatibility or suppressing host immune responses. Our objective was to test an alternative solution comprised of applying a voltage pulse to a microelectrode site, herein termed "rejuvenation." Previously, investigators have reported preliminary electrophysiological results by utilizing a similar voltage pulse. In this study we sought to further explore this phenomenon via two methods: 1) electrophysiology; 2) an equivalent circuit model applied to impedance spectroscopy data. The experiments were conducted via chronically implanted silicon-substrate iridium microelectrode arrays in the rat cortex. Rejuvenation voltages resulted in increased unit recording signal-to-noise ratios (10% +/- 2%), with a maximal increase of 195% from 3.74 to 11.02. Rejuvenation also reduced the electrode site impedances at 1 kHz (67% +/- 2%). Neither the impedance nor recording properties of the electrodes changed on neighboring microelectrode sites that were not rejuvenated. In the equivalent circuit model, we found a transient increase in conductivity, the majority of which corresponded to a decrease in the tissue resistance component (44% +/- 7%). These findings suggest that rejuvenation may be an intervention strategy to prolong the functional lifetime of chronically implanted microelectrodes.


Effects of di- and polysaccharide formulations and storage conditions on survival of freeze-dried Sphingobium sp.
In this study we have compared the ability of the organic polymers Ficoll and hydroxyethylcellulose (HEC) and the disaccharides sucrose and trehalose to support cell survival during freeze-drying and subsequent storage of a gram-negative Sphingobium sp. In addition to determination of viability rates, cell integrity was evaluated using lipid peroxidation and RNA quality assays for the different storage conditions and formulation compositions. All formulations resulted in high initial cell survival rates after freeze-drying. However, the disaccharide formulations were superior to the polymer-based formulations in supporting cell survival during storage with the exception of Ficoll that upon storage under vacuum yielded bacterial survival rates equal to that of sucrose. Storage in the presence of both oxygen and moisture was detrimental for bacterial survival in all formulations tested, however, lipid peroxidation or RNA damages were not the controlling mechanisms for cell death in this system. The ability of Ficoll and HEC to support cell survival during freeze-drying show that organic polymers, expected to lack the water replacing capability of e.g. disaccharides, can successfully be used as lyoprotectants. For storage under vacuum conditions we suggest that the intracellular amount of sugars (i.e. trehalose), or other protective native cell components, is sufficient for a basic protection inside the bacteria cell and that the amorphous state is the most important aspect of the formulation excipient. However, when exposed to oxygen and moisture during storage this protection is not sufficient to prevent cell degeneration.


Roles for common cytokine receptor gamma-chain-dependent cytokines in the generation, differentiation, and maturation of NK cell precursors and peripheral NK cells in vivo.
NK cells differentiate in adult mice from bone marrow hemopoietic progenitors. Cytokines, including those that signal via receptors using the common cytokine receptor gamma-chain (gamma(c)), have been implicated at various stages of NK cell development. We have previously described committed NK cell precursors (NKPs), which have the capacity to generate NK cells, but not B, T, erythroid, or myeloid cells, after in vitro culture or transfer to a fetal thymic microenvironment. NKPs express the CD122 Ag (beta chain of the receptors for IL-2/IL-15), but lack other mature NK markers, including NK1.1, CD49b (DX5), or members of the Ly49 gene family. In this report, we have analyzed the roles for gamma(c)-dependent cytokines in the generation of bone marrow NKP and in their subsequent differentiation to mature NK cells in vivo. Normal numbers of NKPs are found in gamma(c)-deficient mice, suggesting that NK cell commitment is not dependent on IL-2, IL-4, IL-7, IL-9, IL-15, or IL-21. Although IL-2, IL-4, and IL-7 have been reported to influence NK cell differentiation, we find that mice deficient in any or all of these cytokines have normal NK cell numbers, phenotype, and effector functions. In contrast, IL-15 plays a dominant role in early NK cell differentiation by maintaining normal numbers of immature and mature NK cells in the bone marrow and spleen. Surprisingly, the few residual NK cells generated in absence of IL-15 appear relatively mature, expressing a variety of Ly49 receptors and demonstrating lytic and cytokine production capacity.


Evidence based effects of yoga in neurological disorders.
Though yoga is one of the widely used mind-body medicine for health promotion, disease prevention and as a possible treatment modality for neurological disorders, there is a lack of evidence-based review. Hence, we performed a comprehensive search in the PubMed/Medline electronic database to review relevant articles in English, using keywords "yoga and neurological disorder, yoga and multiple sclerosis, yoga and stroke, yoga and epilepsy, yoga and Parkinson's disease, yoga and dementia, yoga and cerebrovascular disease, yoga and Alzheimer disease, yoga and neuropathy, yoga and myelopathy, and yoga and Guillain-Barre syndrome". A total of 700 articles published from 1963 to 14th December 2016 were available. Of 700 articles, 94 articles were included in this review. Based on the available literature, it could be concluded that yoga might be considered as an effective adjuvant for the patients with various neurological disorders.


Body temperature variability (Part 1): a review of the history of body temperature and its variability due to site selection, biological rhythms, fitness, and aging.
Body temperature is a complex, non-linear data point, subject to many sources of internal and external variation. While these sources of variation significantly complicate interpretation of temperature data, disregarding knowledge in favor of oversimplifying complex issues would represent a significant departure from practicing evidence-based medicine. Part 1 of this review outlines the historical work of Wunderlich on temperature and the origins of the concept that a healthy normal temperature is 98.6 degrees F (37.0 degrees C). Wunderlich's findings and methodology are reviewed and his results are contrasted with findings from modern clinical thermometry. Endogenous sources of temperature variability, including variations caused by site of measurement, circadian, menstrual, and annual biological rhythms, fitness, and aging are discussed. Part 2 will review the effects of exogenous masking agents - external factors in the environment, diet, or lifestyle that can influence body temperature, as well as temperature findings in disease states.


Stromelysin 1, neutrophil collagenase, and collagenase 3 do not play major roles in a model of chondrocyte mediated cartilage breakdown.
To determine the collective roles of stromelysin 1, neutrophil collagenase, and collagenase 3 in chondrocyte mediated cartilage proteoglycan and type II collagen degradation in tissue culture model systems. Bovine nasal cartilage explants were cultured with and without recombinant human interleukin 1 alpha (IL-1 alpha), recombinant human tumour necrosis factor alpha, or retinoic acid. Proteoglycan and type II collagen release were determined by colorimetric assay and immunoassay, respectively, in the absence and presence of matrixin inhibitors. Potential toxic effects of the inhibitors were assessed by measuring rates of glycolysis. Loss of proteoglycan and type II collagen from nasal cartilage was inhibited by batimastat, a broad spectrum matrixin inhibitor. BB-3437, a selective inhibitor of stromelysin, neutrophil collagenase, and collagenase 3, at the concentrations used in this study, showed a weak but dose dependent inhibitory effect on the IL-1 stimulated degradation of type II collagen, but had virtually no effect on proteoglycan breakdown. Neither inhibitor affected rates of glycolysis. Stromelysin 1, neutrophil collagenase, and collagenase 3 are unlikely to contribute to chondrocyte mediated proteoglycan degradation in our model system. The modest effect of a selective inhibitor of these enzymes on IL-1 stimulated collagen breakdown suggests a minor role for one or more of these proteinases; potent inhibition by an inhibitor of interstitial collagenase and the gelatinases suggests that these enzymes play a major role in IL-1 stimulated, chondrocyte mediated type II collagen breakdown from nasal cartilage.


Forkhead box protein A2 (FOXA2) protein stability and activity are regulated by sumoylation.
The forkhead box protein A2 (FOXA2) is an important regulator of glucose and lipid metabolism and organismal energy balance. Little is known about how FOXA2 protein expression and activity are regulated by post-translational modifications. We have identified that FOXA2 is post-translationally modified by covalent attachment of a small ubiquitin related modifier-1 (SUMO-1) and mapped the sumoylation site to the amino acid lysine 6 (K6). Preventing sumoylation by mutating the SUMO acceptor K6 to arginine resulted in downregulation of FOXA2 protein but not RNA expression in INS-1E insulinoma cells. K6R mutation also downregulated FOXA2 protein levels in HepG2 hepatocellular carcinoma cells, HCT116 colon cancer cells and LNCaP and DU145 prostate cancer cells. Further, interfering with FOXA2 sumoylation through siRNA mediated knockdown of UBC9, an essential SUMO E2 conjugase, resulted in downregulation of FOXA2 protein levels. Stability of sumoylation deficient FOXA2K6R mutant protein was restored when SUMO-1 was fused in-frame. FOXA2 sumoylation and FOXA2 protein levels were increased by PIAS1 SUMO ligase but not a SUMO ligase activity deficient PIAS1 mutant. Although expressed at lower levels, sumoylation deficient FOXA2K6R mutant protein was detectable in the nucleus indicating that FOXA2 nuclear localization is independent of sumoylation. Sumoylation increased the transcriptional activity of FOXA2 on Pdx-1 area I enhancer. Together, our results show that sumoylation regulates FOXA2 protein expression and activity.


Clinical Study of a Flap Advancement Technique Without Vertical Incision for Guided Bone Regeneration.
The aim of this study was to introduce a novel method of flap advancement without a vertical releasing incision for guided bone regeneration (GBR) and to discuss its clinical outcomes. This retrospective study involved patients who had received GBR for dental implants between April 2012 and April 2013. In all patients, a typical midcrestal incision was made on the edentulous alveolar ridge, and a sulcular incision was extended to the adjacent two teeth; however, no vertical incision was performed. Instead, a wide periosteal releasing incision and an additional releasing incision that selectively cut part of the facial expression muscles (the orbicularis oris or the buccinator) were used. Postoperative complications, such as swelling, pain, paresthesia, signs of infection, and membrane exposure, were evaluated at 1, 2, 4, 12, and 24 weeks after surgery. Forty sites in 34 patients were evaluated. At all surgical sites, flap advancement of more than 7 mm was attained, and clinically passive primary closure was achieved. All patients experienced slight or mild postoperative swelling without functional limitation or discomfort during mouth opening, eye opening, and swallowing. No long-lasting pain (more than a week), paresthesia, or signs of infection occurred during the follow-up period of 6 months. However, delayed exposure of titanium mesh after 4 months was observed in two patients who had used a provisional removable prosthesis. Within 2 weeks, the exposures closed spontaneously after prosthesis use was halted and careful daily dressing was undertaken. The flap advancement technique presented in this study easily enables clinically passive primary closure, and there was no obvious failure of primary closure. This technique could be used successfully in GBR procedures.


BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain.
Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord. Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury. Signalling between microglia and neurons is therefore an essential link in neuropathic pain transmission, but how this signalling occurs is unknown. Here we show that ATP-stimulated microglia cause a depolarizing shift in the anion reversal potential (E(anion)) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (gamma-amino butyric acid), as has been shown to occur after peripheral nerve injury. Applying brain-derived neurotrophic factor (BDNF) mimics the alteration in E(anion). Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the E(anion) shift that follows both nerve injury and administration of ATP-stimulated microglia. ATP stimulation evokes the release of BDNF from microglia. Preventing BDNF release from microglia by pretreating them with interfering RNA directed against BDNF before ATP stimulation also inhibits the effects of these cells on the withdrawal threshold and E(anion). Our results show that ATP-stimulated microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signalling molecule between microglia and neurons. Blocking this microglia-neuron signalling pathway may represent a therapeutic strategy for treating neuropathic pain.


Indirect effects of overfishing on Caribbean reefs: sponges overgrow reef-building corals.
Consumer-mediated indirect effects at the community level are difficult to demonstrate empirically. Here, we show an explicit indirect effect of overfishing on competition between sponges and reef-building corals from surveys of 69 sites across the Caribbean. Leveraging the large-scale, long-term removal of sponge predators, we selected overfished sites where intensive methods, primarily fish-trapping, have been employed for decades or more, and compared them to sites in remote or marine protected areas (MPAs) with variable levels of enforcement. Sponge-eating fishes (angelfishes and parrotfishes) were counted at each site, and the benthos surveyed, with coral colonies scored for interaction with sponges. Overfished sites had >3 fold more overgrowth of corals by sponges, and mean coral contact with sponges was 25.6%, compared with 12.0% at less-fished sites. Greater contact with corals by sponges at overfished sites was mostly by sponge species palatable to sponge predators. Palatable species have faster rates of growth or reproduction than defended sponge species, which instead make metabolically expensive chemical defenses. These results validate the top-down conceptual model of sponge community ecology for Caribbean reefs, as well as provide an unambiguous justification for MPAs to protect threatened reef-building corals. An unanticipated outcome of the benthic survey component of this study was that overfished sites had lower mean macroalgal cover (23.1% vs. 38.1% for less-fished sites), a result that is contrary to prevailing assumptions about seaweed control by herbivorous fishes. Because we did not quantify herbivores for this study, we interpret this result with caution, but suggest that additional large-scale studies comparing intensively overfished and MPA sites are warranted to examine the relative impacts of herbivorous fishes and urchins on Caribbean reefs.


Overanticoagulation is associated with renal function decline.
Recent studies suggest that overanticoagulation impairs renal function in patients on warfarin therapy, due to renal tubular obstruction from glomerular hemorrhage. Data from the Rotterdam Study (The Netherlands), a prospective population-based cohort study of patients 55 years and older, were used for this study. Information on vitamin K antagonist (VKA) therapy was obtained from the regional anticoagulation clinic, where prothrombin times were monitored every 1-6 weeks depending on target level and stability of the international normalized ratio (INR). Linear regression was performed to study the association between the cumulative number of instances of overanticoagulation (defined as a measurement of an INR >6.0) and the change in renal function between baseline and third examination round based on estimated glomerular filtration rate (CKD-EPI equation). Age, sex, baseline renal function, baseline and incident heart failure, and indication for VKA therapy were included as potential confounders. Information was available for analysis on 2,802 study participants in whom overanticoagulation was significantly associated with a decline in renal function, after adjustment for confounding by age, sex, heart failure, baseline glomerular filtration rate and indication for VKA therapy (-0.180 ml/min per 1.73 m(2) per year per event for INR >6.0, p = 0.030). Overanticoagulation (INR >6.0) is associated with a decline in renal function. Further studies are needed to evaluate the causal role of different degrees of overanticoagulation, including transient effects, in high-risk groups, and the association with the new oral anticoagulants.


Effect of low-compression balls on wheelchair tennis match-play.
The purpose of this study was to compare court-movement variables and physiological responses to wheelchair tennis match-play when using low vs. standard compression tennis balls. Eleven wheelchair basketball players were monitored during repeated bouts of tennis (20 min) using both ball types. Graded and peak exercise tests were completed. For match-play, a data logger was used to record distance and speed. Individual linear heart rate oxygen consumption relationships were used to estimate match-play oxygen uptake. Significant main effects for ball type revealed that total distance (P<0.05), forward distance (P<0.05), and average speed (P<0.05) were higher for play using a low-compression ball. A lower percentage of total time was spent stationary (P<0.001), with significantly more time spent at speeds of 1-1.49 (P<0.05), 1.5-1.99 (P<0.05) and 2.0-2.49 (P<0.05) m ∙ sec(-1) when using the low-compression ball. Main effects for physiological variables were not significant. Greater total and forward distance, and higher average speeds are achieved using a low-compression ball. The absence of any difference in measured HR and estimated physiological responses would indicate that players move further and faster at no additional mean physiological cost. This type of ball will be useful for novice players in the early phases of skill development.


Health care professionals implementing a smoke-free policy at inpatient psychiatric units.
Smoke-free grounds policies (SFGPs) were introduced to inpatient psychiatric hospital settings to improve health among patients, staff, and visitors. We conducted an ethnographic study in Northern British Columbia, Canada, to describe how the implementation of SFGPs is affected by institutional cultures. Data reported here included participant observation, document review, informal discussions (n = 11), and interviews with health care professionals (HCPs; n = 19) and staff (n = 2) at two hospitals. We used iterative and inductive processes to derive thematic findings. Findings related to HCPs illustrate how local contexts and cultural factors affect SFGP implementation. These factors included individual beliefs and attitudes, the influence of group norms, leadership and consensus building, and locale-specific norms. Strong, consultative leadership, in which leaders solicited input from and long-term support of people most directly responsible for policy implementation, was key to success.


Effect of ω-3 polyunsaturated fatty acid on toll-like receptors in patients with severe multiple trauma.
This study examined the effects of ω-3 polyunsaturated fatty acid (ω-3PUFA) on the expression of toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4) and some related inflammatory factors in peripheral blood mononuclear cells (PBMCs) of patients with early-stage severe multiple trauma. Thirty-two patients who were admitted to the Department of Traumatic Surgery, Tongji Hospital (Wuhan, China) between May 2010 and November 2010, and diagnosed as having severe multiple trauma with a injury severity score (ISS) no less than 16, were enrolled in the study and divided into two groups at random (n=16 in each): ω-3PUFA group and control group in which routine parenteral nutrition supplemented with ω-3PUFA or not was administered to the patients in two groups for consecutive 7 days. Peripheral blood from these patients was collected within 2 h of admission (day 0), and 1, 3, 5 and 7 days after the nutritional support. PBMCs were isolated and used for detection of the mRNA and protein expression of TLR2 and TLR4 by using real-time PCR and flow cytometry respectively, the levels of NF-κB by quantum dots-based immunofluorescence assay, the levels of TNF-α, IL-2, IL-6 and COX-2 by ELISA, respectively. The results showed that the mRNA and protein expression of TLR2 and TLR4 in PBMCs was significantly lower in ω-3PUFA group than in control group 5 and 7 days after nutrition support (both P<0.05). The levels of TNF-α, IL-2, IL-6 and COX-2 were found to be substantially decreased in PBMCs in ω-3PUFA group as compared with control group at 5th and 7th day (P<0.05 for all). It was concluded that ω-3PUFA can remarkably decrease the expression of TLR2, TLR4 and some related inflammatory factors in NF-κB signaling pathway in PBMCs of patients with severe multiple trauma, which suggests that ω-3PUFA may suppress the excessive inflammatory response meditated by the TLRs/NF-κB signaling pathway.


Conserved roles for yeast Rho1 and mammalian RhoA GTPases in clathrin-independent endocytosis.
Eukaryotic cells use numerous endocytic pathways for nutrient uptake, protein turnover and response to the extracellular environment. While clathrin-mediated endocytosis (CME) has been extensively studied in yeast and mammalian cells, recent studies in higher eukaryotes have described multiple clathrin-independent endocytic pathways that depend upon Rho family GTPases and their effector proteins. In contrast, yeast cells have been thought to rely solely on CME. In a recent study, we used CME-defective yeast cells lacking clathrin-binding endocytic adaptor proteins in a genetic screen to identify novel factors involved in endocytosis. This approach revealed the existence of a clathrin-independent endocytic pathway involving the GTPase Rho1, which is the yeast homolog of RhoA. Further characterization of the yeast Rho1-mediated endocytic pathway suggested that the Rho1 pathway requires additional proteins that appear to play conserved roles in RhoA-dependent, clathrin-independent endocytic pathways in mammalian cells. Here, we discuss the parallels between the yeast Rho1-dependent and mammalian RhoA-dependent endocytic pathways, as well as the applications of yeast as a model for studying clathrin-independent endocytosis in higher eukaryotes.